title: Methyl-thiazoles: a novel mode of inhibition with the potential to develop novel inhibitors targeting InhA in Mycobacterium tuberculosis.
abstract: InhA is a well validated Mycobacterium tuberculosis (Mtb) target as evidenced by the clinical success of isoniazid. Translating enzyme inhibition to bacterial cidality by targeting the fatty acid substrate site of InhA remains a daunting challenge. The recent disclosure of a methyl-thiazole series demonstrates that bacterial cidality can be achieved with potent enzyme inhibition and appropriate physicochemical properties. In this study, we report the molecular mode of action of a lead methyl-thiazole, along with analogues with improved CYP inhibition profile. We have identified a novel mechanism of InhA inhibition characterized by a hitherto unreported "Y158-out" inhibitor-bound conformation of the protein that accommodates a neutrally charged "warhead". An additional novel hydrophilic interaction with protein residue M98 allows the incorporation of favorable physicochemical properties for cellular activity. Notably, the methyl-thiazole prefers the NADH-bound form of the enzyme with a Kd of ~13.7 nM, as against the NAD(+)-bound form of the enzyme.
authors.affiliation: Department of Medicinal Chemistry, ‡Department of Biosciences, AstraZeneca India Pvt. Ltd. , Bellary Road, Hebbal, Bangalore-560024, India.
authors.forename: Pravin S
authors.initials: PS
authors.lastname: Shirude
authors.forename: Prashanti
authors.initials: P
authors.lastname: Madhavapeddi
authors.forename: Maruti
authors.initials: M
authors.lastname: Naik
authors.forename: Kannan
authors.initials: K
authors.lastname: Murugan
authors.forename: Vikas
authors.initials: V
authors.lastname: Shinde
authors.forename: Radha
authors.initials: R
authors.lastname: Nandishaiah
authors.forename: Jyothi
authors.initials: J
authors.lastname: Bhat
authors.forename: Anupriya
authors.initials: A
authors.lastname: Kumar
authors.forename: Shahul
authors.initials: S
authors.lastname: Hameed
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Holdgate
authors.forename: Gareth
authors.initials: G
authors.lastname: Davies
authors.forename: Helen
authors.initials: H
authors.lastname: McMiken
authors.forename: Naina
authors.initials: N
authors.lastname: Hegde
authors.forename: Anisha
authors.initials: A
authors.lastname: Ambady
authors.forename: Janani
authors.initials: J
authors.lastname: Venkatraman
authors.forename: Manoranjan
authors.initials: M
authors.lastname: Panda
authors.forename: Balachandra
authors.initials: B
authors.lastname: Bandodkar
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.forename: Jon A
authors.initials: JA
authors.lastname: Read
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000201:enzymology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D013844:Thiazoles; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium